Functions of O-fucosyltransferase in Notch trafficking and signaling: towards the end of a controversy?

Abstract

The precise role of the O-fucosyltransferase Ofut1 in Notch-receptor trafficking has remained controversial. A recent study sheds new light on the non-catalytic activity of Ofut1 and provides further evidence that Ofut1 acts as a chaperone in the endoplasmic reticulum.

Figure 1

O-fucosylation of Notch and functions of Ofut1. (a) Schematic representation of the Drosophila Notch receptor. The extracellular domain (NECD) is composed of three Lin12/Notch repeats (LNRs) (black) and 36 EGF-like repeats; the EGF repeats are predicted to be either O-glucosylated (cyan), O-fucosylated (yellow) or doubly modified (green) adapted from [19]. The S2 cleavage site is indicated by an arrow. The intracellular domain (NICD) contains various elements involved in transcriptional activation: a RAM domain, seven ankyrin repeats (ANK), a transactivation domain (TAD) and a PEST domain (P). TM, transmembrane domain. (b,c) Two models for the roles of Ofut1 in Notch trafficking. Each model is illustrated in a schematic cell that is shown as wild type on the left and ofut1 mutant on the right, gray-shaded side. (b) Model 1: in the ER, newly synthesized, unfolded Notch (with the NECD in red and the NICD in white) becomes properly folded (NECD in green) and is O-fucosylated by Ofut1 (yellow diamond). It is then transported to the plasma membrane and adherens junctions (AJs, cyan) through the Golgi. In the absence of Ofut1, Notch remains unfolded and is retained in the ER. (c) Model 2: O-fucosylated Notch is first transported via the Golgi to the apical membrane and then transported to AJs by a transcytosis mechanism. In ofut1 mutant cells, Notch goes to the membrane, is internalized and accumulates in an uncharacterized endocytic compartment.